The bioelectrical interactions and activity believed to be present in a variety of biological tissues and cells are one of the least understood of the physiological processes. However, there has recently been much research into these interactions and activities related to the growth and repair of certain tissues and cells. In particular, there has been considerable interest in stimulation by electric and electromagnetic fields and their effect on the growth and repair of bone and cartilage. Scientists believe that such research might be useful in the development of new treatments for a variety of medical problems.
Osteoarthritis, also known as degenerative joint disease, is characterized by degeneration of articular cartilage as well as proliferation and remodeling of subchondral bone. The usual symptoms are stiffness, limitation of motion, and pain. Osteoarthritis is the most common form of arthritis, and prevalence rates increase markedly with age. It has been shown that elderly patients with self-reported osteoarthritis visit doctors twice as frequently as their unaffected peers. Such patients also experience more days of restricted activity and bed confinement compared to others in their age group. In one study, the majority of symptomatic patients became significantly disabled during an 8-year follow-up period (Massardo et al., Ann Rheum Dis 48:893–897, 1989).
Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the primary treatment modality for osteoarthritis. It is unknown whether the efficacy of NSAIDs is dependent upon their analgesic or anti-inflammatory properties or the slowing of degenerative processes in the cartilage. There is also a concern that NSAIDs may be deleterious to patients. For example, NSAIDs display well-known toxic effects in the stomach, gastrointestinal tract, liver and kidney. Moreover, aspirin inhibits proteoglycan synthesis and normal cartilaginous repair processes in animals. One study in humans also suggested that indomethacin might accelerate breakdown of hip cartilage. All adverse effects appear more commonly in the elderly—the very population most susceptible to osteoarthritis.
In the disease commonly known as osteoporosis, bone demineralizes and becomes abnormally rarefied. Bone comprises an organic component of cells and matrix as well as an inorganic or mineral component. The cells and matrix comprise a framework of collagenous fibers that is impregnated with the mineral component of calcium phosphate (85%) and calcium carbonate (10%) that imparts rigidity to bone. While osteoporosis is generally thought to afflict the elderly, certain types of osteoporosis may affect persons of all ages whose bones are not subject to functional stress. In such cases, patients may experience a significant loss of cortical and cancellous bone during prolonged periods of immobilization. Elderly patients are known to experience bone loss due to disuse when immobilized after fracture of a bone; this may ultimately lead to a secondary fracture in an already osteoporotic skeleton. Diminished bone density may lead to collapse of vertebrae, fractures of hips, lower arms, wrists and ankles, as well as incapacitating pains. Alternative non-surgical therapies for such diseases are needed.
Pulsed electromagnetic fields (PEMFs) and capacitive coupling (CC) have been used widely to treat non-healing fractures and related problems in bone healing since approval by the Food and Drug Administration in 1979. The original basis for the trial of this form of therapy was the observation that physical stress on bone causes the appearance of tiny electric currents that, along with mechanical strain, were thought to be the mechanisms underlying transduction of the physical stress into a signal that promotes bone formation. Along with direct electric field stimulation that was successful in the treatment of nonunion bone fractures, noninvasive technologies using PEMF and CC (where the electrodes are placed on the skin in the treatment zone) were also found to be effective. PEMFs generate small, induced currents (Faraday currents) in the highly conductive extracellular fluid, while CC directly causes currents in the tissues; both PEMFs and CC thereby mimic endogenous electrical currents.
The endogenous electrical currents, originally thought to be due to phenomena occurring at the surface of crystals in the bone, have been shown to be due primarily to movement of fluid containing electrolytes in channels of the bone containing organic constituents with fixed negative charges, generating what are called “streaming potentials.” Studies of electrical phenomena in cartilage have demonstrated a mechanical-electrical transduction mechanism that resembles those described in bone, appearing when cartilage is mechanically compressed, causing movement of fluid and electrolytes over the surface of fixed negative charges in the proteoglycans and collagen in the cartilage matrix. These streaming potentials apparently serve a purpose in cartilage similar to that in bone, and, along with mechanical strain, lead to signal transduction that is capable of stimulating chondrocyte synthesis of matrix components.
The main application of direct current, CC, and PEMFs has been in orthopaedics in the healing of nonunion bone fractures (Brighton et al. J Bone Joint Surg 1981;63:2–13; Brighton and Pollack J Bone Joint Surg 1985;67:577–585; Bassett et al. Crit Rev Biomed Eng 1989;17:451–529; Bassett et al. J Am Med Assoc 1982;247:623–628). Clinical responses have been reported in avascular necrosis of hips in adults and Legg-Perthe's disease in children (Bassett et al. Clin Orthop 1989;246:172–176; Aaron et al. Clin Orthop 1989;249:209–218; Harrison et al. J Pediatr Orthop 1984;4:579–584, 1984). It has also been shown that PEMFs (Mooney. Spine 1990;15:708–712) and CC (Goodwin et al. Spine 1999;24:1349–135) can significantly increase the success rate of lumbar fusions. There are also reports of augmentation of peripheral nerve regeneration and function and promotions of angiogenesis (Bassett. Bioessays 1987;6:36–42). Patients with persistent rotator cuff tendonitis refractory to steroid injection and other conventional measures showed significant benefit compared with placebo treated patients (Binder et al. Lancet 1984;695–698). Finally, Brighton et al., have shown in rats the ability of an appropriate CC electric field to both prevent and reverse vertebral osteoporosis in the lumbar spine (Brighton et al. J Orthop Res 1988;6:676–684; Brighton et al. J Bone Joint Surg 1989;71:228–236).
More recently, research in this area has focused on the effects that stimulation has on tissues and cells. For example, it has been conjectured that direct currents do not penetrate cellular membranes and that control is achieved via extracellular matrix differentiation (Grodzinsky Crit Rev Biomed Eng 1983;9:133). In contrast to direct currents, it has been reported that PEMFs can penetrate cell membranes and either stimulate them or directly affect intracellular organelles. An examination of the effect of PEMFs on extracellular matrices and in vivo endochondral ossification found increased synthesis of cartilage molecules and maturation of bone trabeculae (Aaron et al. J Bone Miner Res 1998;4:227–233). More recently, it was reported (Lorich et al. Clin Orthop Related Res 1998;350:246–256) that signal transduction of a capacitively coupled electric signal is via voltage-gated calcium channels, leading to an increase in cytosolic calcium with a subsequent increase in activated (cytoskeletal) calmodulin.
Much research has been performed using tissue culture techniques in order to understand the mechanisms of response. In one study, it was found that electric fields increased [3H]thymidine incorporation into the DNA of chondrocytes, supporting the notion that Na+ and Ca+2 fluxes generated by electrical stimulation trigger DNA synthesis (Rodan et al. Science 1978;199:690–692). Studies have found changes in the second messenger, cAMP, and cytoskeletal rearrangements due to electrical perturbations (Ryaby et al. Trans BRAGS 1986;6; Jones et al. Trans. BRAGS 6:51, 1986; Brighton and Townsend J Orthop Res 1988;6:552–558). Other studies have found effects on glycosaminoglycan, sulfation, hyaluronic acid, lysozyme activity and polypeptide sequences (Norton et al. J Orthop Res 1988;6:685–689; Goodman et al. Proc Natl Acad Sci 1988;85:3928–3932).
It was reported in 1996 by one of the present inventors that a cyclic, biaxial 0.17% mechanical strain produces a significant increase in TGF-β1 mRNA in cultured MC3T3-E1 bone cells (Zhuang et al. Biochem Biophys Res Commun 1996;229:449–453). Several significant studies followed in 1997. In one study it was reported that the same cyclic, biaxial 0.17% mechanical strain produced a significant increase in PDGF-A mRNA in similar bone cells (Wang et al. Biochem Mol Biol Int 1997;43:339–346). It was also reported that a 60 kHz capacitively coupled electric field of 20 mV/cm produced a significant increase in TGF-β1 mRNA in similar bone cells (Zhuang et al. Biochem Biophys Res Commun 1997;237:225–229). However, the effect such a field would have on other genes has not been reported in the literature.
In the above-referenced parent patent application, entitled “Regulation of Genes Via Application of Specific and Selective Electrical and Electromagnetic Signals, ” methods were disclosed for determining the specific and selective electrical and electromagnetic signals for use in creating specific and selective fields for regulating target genes of diseased or injured tissues. The present invention builds upon the technique described therein by describing the method of determining the voltage and current output required, and the corresponding apparatus for delivering specific and selective electrical and electromagnetic signals to the human hip joints in patients afflicted with osteoarthritis and other cartilage defects, diseases and injuries.